Biweekly mXELIRI versus FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (EXIST): A multicenter, randomized, open-label, phase 2 study.
Authors: Zhichao Jiang, Deng Wei, Yongkun SUN, Jianping Cheng, Wen Zhang, Chunmei Bai, Zuoxing Niu, Chunrong Zhu, Rong Wu, Xiaobing Chen, Yan Zhang, Sheng Li, Yingying Huang, Jianfeng Zhou, Shengbin Shi, Feng Xiong, Yun-Bo Zhao, Liangjun Zhu, Ai-Ping Zhou
Journal: Journal of Clinical Oncology (2022)

3594 Background: Irinotecan and fluorouracil are the most effective drugs in the treatment of metastatic colorectal cancer (mCRC). But XELIRI (irinotecan plus capecitabine) has not been recommended in the 1 st -L setting due to the toxicity in the Western countries. While, modified 3-weekly XELIRI has been proved to be effective and safe in the 2 nd -L therapy in Asian mCRC patients. Therefore, this study aimed to assess the efficacy and safety of biweekly mXELIRI with reduced dose of irinotecan in the 1 st -L treatment of mCRC. Methods: This was a randomized, open-label, non-inferiority study undertaken at 11 hospitals in China. Eligible patients were aged ≥18 years with unresectable metastatic histologically diagnosed colorectal adenocarcinoma; had an ECOG of 0 or 1 and at least one measurable disease according to the RECIST v 1.1 without any systemic chemotherapy for metastatic disease. Patients were randomly assigned (1:1) stratified by the location of primary tumor (left or right site) to receive 9 cycles of mXELIRI + bevacizumab (Bev) (irinotecan 150mg/m 2 D1, capecitabine 1000mg/m 2 bid D1-10, Bev 5mg/kg D1, Q2W) or FOLFIRI + Bev (irinotecan 180mg/m 2 D1, CF 400mg/m 2 D1, 5-Fu 400mg/m 2 bolus D1, 5-Fu 2400mg/m 2 civ 46h D1, Bev 5mg/kg D1, Q2W) followed by maintenance treatments with capecitabine + Bev or 5-FU + CF + Bev. The primary endpoint was 12-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), PFS, overall survival (OS) and safety. Results: From May, 2018 to Apr, 2021, 264 pts were randomized (mXELIRI + Bev 132; FOLFIRI + Bev 132). The median age was 61 (29-80) years old. 62.5% of the patients were men. With a median follow-up of 17.1 months, the 12-month PFS rates were 43.9% vs. 28.8% in the mXELIRI + Bev and FOLFIRI + Bev groups, respectively. The HR was 0.72 (95%CI 0.51 -1.02) which didn’t cross the predefined non-inferiority margin of 1.18 (upper bound &lt; 1.18). The median PFS were 10.5 months vs. 9.6 months (p = 0.056, HR 0.74, 95%CI 0.55-1.01). The median OS was still not mature. The ORR were 51.5% vs. 47.0% (p = 0.460), respectively. The incidence of treatment related adverse events (TRAEs) between these two groups were similar. The most common TRAEs were neutropenia (mXELIRI + Bev vs. FOLFIRI + Bev: 51.8% vs. 57.0%), leukopenia (43.9% vs. 55.3%), anemia (54.4% vs. 45.6%), nausea (31.6% vs. 40.4%), ALT/AST increased (22.8% vs. 23.7%), diarrhea (21.1% vs. 16.7%), fatigue (20.2% vs. 23.7%), vomiting (17.5% vs. 20.2%) and hyperbilirubinemia (14.9% vs. 17.5%). No treatment- related deaths were reported. Conclusions: Biweekly mXELIRI with reduced dose of irinotecan plus bevacizumab was noninferior to the standard dose of FOLFIRI + Bev in PFS, with similar safety profile in the patients with untreated mCRC. Clinical trial number: NCT04247984. Research Sponsor: No Clinical trial information: NCT04247984.